Tracers labeled with short-lived positron emitting radionuclides (e.g. 11C, t1/2=20.3 min) are frequently used in various non-invasive in vivo studies in combination with positron emission tomography (PET). Because of the radioactivity, the short half-lives and the submicromolar amounts of the labeled substances, extraordinary synthetic procedures are required for the production of these tracers. An important part of the elaboration of these procedures is development and handling of new 11C-labeled precursors. This is important not only for labeling new types of compounds, but also for increasing the possibility of labeling a given compound in different positions. Throughout the development of a synthetic labeling method using short-lived radionuclides, the recognition of time as a parameter in the same category as chemical yield is important.
During the last two decades carbonylation chemistry using carbon monoxide has developed significantly. The recent development of methods such as palladium-catalyzed carbonylative coupling reactions has provided a mild and efficient tool for the transformation of carbon monoxide into different carbonyl compounds.
Carbonylation reactions using [11C]carbon monoxide has a primary value for PET-tracer synthesis since biologically active substances often contain carbonyl groups or functionalities that can be derived from a carbonyl group. The syntheses are tolerant to most functional groups, which means that complex building blocks can be assembled in the carbonylation step to yield the target compound. This is particularly valuable in PET-tracer synthesis where the unlabeled substrates should be combined with the labeled precursor as late as possible in the reaction sequence, in order to decrease synthesis-time and thus optimize the uncorrected radiochemical yield.
When compounds are labeled with 11C, it is usually important to maximize specific radioactivity. In order to achieve this, the isotopic dilution and the synthesis time must be minimized. Isotopic dilution from atmospheric carbon dioxide may be substantial when [11C]carbon dioxide is used in a labeling reaction. Due to the low reactivity and atmospheric concentration of carbon monoxide (0.1 ppm vs. 3.4×104 ppm for CO2), this problem is reduced with reactions using [11C]carbon monoxide.
The synthesis of [11C]carbon monoxide from [11C]carbon dioxide using a heated column containing reducing agents such as zinc, charcoal or molybdenum has been described previously in several publications.
The cold-trap technique is widely used in the handling of 11C-labeled precursors, particularly in the case of [11C]carbon dioxide. The procedure has, however, only been performed in one single step and the labeled compound was always released in a continuous gas-stream simultaneous with the heating of the cold-trap. Furthermore, the volume of the material used to trap the labeled compound has been relative large in relation to the system to which the labeled compound has been transferred. Thus, the option of using this technique for radical concentration of the labeled compound and miniaturization of synthesis systems has not been explored. This is especially noteworthy in view of the fact that the amount of a 11C-labelled compound usually is in the range 20-60 nmol.
Recent technical development for the production and use of [11C]carbon monoxide has made this compound useful in labeling synthesis. WO 02/102711 describes a system and a method for the production and use of a carbon-isotope monoxide enriched gas-mixture from an initial carbon-isotope dioxide gas mixture. [11C]Carbon monoxide may be obtained in high radiochemical yield from cyclotron produced [11C]carbon dioxide and can be used to yield target compounds with high specific radioactivity. This reactor overcomes the difficulties listed above and is useful in synthesis of 11C-labelled compounds using [11C]carbon monoxide in palladium or selenium mediated reaction. With such method, a broad array of carbonyl compounds can be labeled (Kilhlberg, T.; Langstrom, B. J., Org. Chem. 64, 1999, 9201-9205. Kihlberg, T.; Karimi, F.; Langstrom, B., J., Org. Chem. 67, 2002, 3687-3692).
Carbamoyl groups are common in biologically active compounds such as pharmaceuticals and are thus an important target for 11C-labeling. The selenium mediated reactions for synthesis of carbamoyl compounds are, however, limited to the use of strongly nucleophilic primary amines or favorable ring closures. [11C]Phosgen on the other hand is very reactive and can be used to label in principle all types of carbamoyl compounds. For this reason, the use of [11C]phosgen has been the most common approach for 11C-labeling of carbamoyl compounds.
The existing methods for [11C]phosgen production, however, have many disadvantages. For example, [11C]phosgen can be made in flow from [11C]carbon monoxide with PtCl4 as the chlorinating agent at elevated temperatures (Roeda, D., Crouzel, C. and Van Zanten, B., Radiochem. Radioanal. Lett., 33, 175 (1978)). However, to obtain reproducible results using this approach, temperature control is very critical and difficult, and the yield is not particularly high. In addition, it became clear that this procedure gives rise to a considerable amount of carrier phosgen, arising from inactive carbon monoxide already present in PtCl4.
Another approach is described by Roeda et al (Roeda, D., Westera, G., International Journal of Applied Radiation & Isotope., 931-932, Vol. 32, 1981). It uses an in-flow [11C]phosgen production system, using the reaction of [11C]carbon monoxide with chlorine gas induced by UV radiation. However, this approach uses a system with a continuous gas flow with relatively large volume and amount of chlorine. The consequences are that the system is bulky and the method gives relatively low levels of specific radioactivity, since the chlorine gas seams to be a major source of carrier phosgene.
Also other methods, based on the use of [11C]methane, suffers from low levels of specific radioactivity as well as complicated and capricious synthesis systems.
Therefore, there is a need for a system and method in order to overcome the problems listed above and provide target structures to further increase the utility of [11C]phosgen as an important starting material in preparing useful PET tracers.
Discussion or citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.